Protein phosphatase 2A (“PP2A”) is a ubiquitous and conserved serine/threonine phosphatase with broad substrate specificity and diverse cellular functions. PP2A typically exists as heterotrimers comprising of catalytic C-, structural or scaffold A- and regulatory B-type subunits, belonging to the B, B′ B″ and B′″ families. In vivo, a major proportion of the A- and C-subunits form a stable heterodimer, which is also referred to as the core enzyme, (see Price, N. E., and Mumby, M. C. Biochemistry 39, 11312-11318 (2000)). The B-type subunits direct substrate-specificity and sub-cellular localization. The heterotrimeric holoenzyme assembly with specific B-type subunits results in PP2A specificity, in the modulation of kinetic properties of PP2A to different substrates (see Price, N. E., and Mumby, M. C. Biochemistry 39, 11312-11318 (2000)) and therefore is likely to affect PP2A enzyme activity towards those substrates.
The alpha-carboxyl of the C-terminal leucine residue of the catalytic subunit of PP2A is subject to reversible methyl esterification and methyl-ester hydrolysis, and the methylaton state of PP2A regulates heterotrimer assembly, [see Tokstykh, T. et al., EMBO J. 19 (21): 5682-91 (2000); Wu, J. et al, EMBO J. 19 (21): 5672-81 (2000); Wei, H. et al. J. Biol. Chem. 276 (2): 1570-77 (2001); and Yu, X. X. et al, Mol. Biol. Cell 12 (1): 185-99 (2001)]. The carboxyl methylation requires an S-adenosyl-methionine (SAM) dependent methyltransferase (MT, MTase, LCMT or PPMT) (see Lee, J., and Stock, J. J. Biol. Chem. 268, 19192-19195 (1993)), which recognizes SAM and the AC heterodimer or the heterotrimeric holoenzyme (but not C subunit alone) as substrates. Methylated PP2A is demethylated by a specific methylesterase (ME, MEase, PME1 or PPME) (see Lee, J., Chen, Y., Tolstykh, T., and Stock, J. P.N.A.S. U.S.A. 93, 6043-6047. (1996)).
As a universal regulator of cellular functions, PP2A is essential for normal biological activities. Malfunction of PP2A is associated with a wide variety of disease conditions. Alterations in PP2A methylation and/or activity are associated with various disorders, diseases, and conditions, including, among others, neurological disorders, neurodegenerative diseases, diabetes, insulin resistance, and metabolic syndrome.
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